Synthesis of 6-substituted 6-nitroperhydro-1,4-diazepines via novel tandem retro-Henry and Mannich/Michael reactions

Article abstract of DOI:10.1021/ol203101s

N,N′-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substitu

Full text of DOI:10.1021/ol203101s

ORGANIC
LETTERS
2012
Vol. 14, No. 3
716–719
Synthesis of 6-Substituted
6-Nitroperhydro-1,4-diazepines via
Novel Tandem Retro-Henry and
Mannich/Michael Reactions
Jonathan Martinelli, Giuseppe Gugliotta, and Lorenzo Tei*
ꢀ
Dipartimento di Scienze e Innovazione Tecnologica, Universita del Piemonte Orientale
“A. Avogadro”, Viale T. Michel 11, 15121 Alessandria, Italy
lorenzo.tei@mfn.unipmn.it
Received November 30, 2011
ABSTRACT
N,N0-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael
reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-diazepines.
The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective
hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved.
The optimization and differentiation of the synthesis
of variously substituted heterocycles can be considered as a
key target in the development of novel drugs, since hetero-
cyclic rings constitute the core of many biologically active
compounds. Among them, 1,4-diazepines are of consider-
able importance due to their wide spectrum of biological
and pharmacological activities.1 In recent years, a variety
of 1,4-diazepines have been regarded as peptidomimetic
scaffolds with a conformationally constrained core,2 anti-
HIV agents,3 and inhibitors of protein kinase, caspase and
matrix metalloproteinase.4 Moreover, several functiona-
lized1,4-diazepinesarereportedtobeunderclinicalstudies
for treatment of several pathologies, e.g., overactive blad-
der or urge urinary incontinence, schizophrenia, obesity,
nausea, and vomiting.5 More particularly, the family of
6-aminoperhydro-1,4-diazepines are well-known seroto-
nin and dopamine receptor antagonists: for example, their
benzamides derivatives with alkyl groups at the 1 and
4 ring nitrogen atoms have been proposed as broad
(1) Ramajayam, R.; Giridhar, R.; Yadav, M. R. Mini-Rev. Med.
Chem. 2007, 7, 793.
(2) Taillefumier, C.; Thielges, S.; Chapleur, Y. Tetrahedron 2004, 60,
2213.
(3) Janin, Y. L.; Aubertin, A. M.; Chiaroni, A.; Riche, C.; Monneret,
C.; Bisagani, E.; Grierson, D. S. Tetrahedron 1996, 52, 15157.
(4) (a) Lakatosh, S. A.; Luzikov, Y. N.; Preobrazhenskaya, M. N.
Org. Biomol. Chem. 2003, 1, 826. (b) Mondragon, L.; Orzaez, M.;
Sanclimens, G.; Moure, A.; Arminan, A.; Sepulveda, P.; Messeguer,
A.; Vicent, M. J.; Perez-Paya, E. J. Med. Chem. 2008, 51, 521. (c) Zhang,
Y. M.; Fan, X.; Yang, S. M.; Scannevin, R. H.; Burke, S. L.; Rhodes,
K. J.; Jackson, P. F. Bioorg. Med. Chem. Lett. 2008, 18, 405.
(5) (a) Dvorak, C. A.; Fisher, L. E.; Green, K. L.; Stabler, R. S.;
Maag, H.; Prince, A.; Repke, D. B.; Harris, R. N. III. WO 2001090081,
2001. (b) Ramamoorthy, S. P. WO 2003091250, 2003. (c) Harada, H.;
Morie, T.; Kato, S. Chem. Pharm. Bull. 1998, 46, 1160. (d) Yoshida, N.
J. Pharmacol. Exp. Ther. 1992, 260, 1159.
r
10.1021/ol203101s
Published on Web 01/19/2012
2012 American Chemical Society

antiemetic agents as they show a potent dopamine D2 and
5-HT3 receptors inhibitory activity.6 These heterocycles
have also been employed as ligands for transition metal ion
coordination7 and used as bleach catalysts or to support
cationic group 3 metal alkyl catalysts.8 Moreover, the
gadolinium(III)-complex of the tetraacetic acid derivative
of 6-methyl-6-amino-1,4-perhydrodiazepine (AAZTA)
was reported as an efficient contrast agent for magnetic
resonance imaging.9 The insertion of various groups at the
6-position would differentiate the biological activity of this
versatile heterocycle and would also permit the synthesis of
AAZTA derivatives containing various functional groups
useful for bioconjugation and relevant for the future
development of efficient molecular imaging probes.10
In parallel, there is great current interest in the develop-
ment of new tandem and multicomponent domino reac-
tions in order to introduce not only high molecular
complexity and diversity but also matched functionalities
suitable for further transformations or for the conjuga-
tion to biomolecules. Actually, the combination of such
reactions with an efficient post-transformation, typically
a ring-forming process, has proved to be a powerful tool
for the synthesis of highly functionalized heterocyclic
compounds.11
can be applied to β-nitro alcohols14 and, as shown by
Harada et al.,15 to 6-hydroxymethyl-6-nitroperhydrodia-
zepines in order to replace the hydroxymethyl group with a
hydrogen atom. The stable carbanion/nitronate 2(Scheme 1)
was formed in a few minutes by reaction of 1 with a slight
excess of t-BuOK in THF. Owing to the resonance stabi-
lization, 2 can be isolated and characterized by spectro-
scopic techniques (see the Supporting Information for
details). In particular, the 13C NMR spectrum in CD3OD
clearly shows that 2 exists as a nitronate with the CdN
carbon resonating at 121.7 ppm. This was also confirmed
by IR spectroscopy, which shows a strong peak at 1597 cmꢀ1
assigned to the CdN stretching of the nitronate, whereas
the tertiary aliphatic nitro group in 1 is observed at around
1535 cmꢀ1
.
Scheme 1. Formation of the Carbanion/Nitronate Intermediate
We have recently reported the fast and easy synthesis of
1,4-dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diaze-
pine (1) by double nitro-Mannich reaction between N,N0-
dibenzylethylenediamine, paraformaldehyde, and 2-nitro-
ethanol in nearly quantitative yield.12 Herein we account
for the preparation of a series of derivatives obtained from
1 via novel cascade sequences initiated by a retro-Henry
reaction followed by either a Michael or a Mannich reac-
tion. The versatility of these approaches was tested with
several acrylic derivatives and with different primary and
secondary amines.
We thought to use such a species as a nucleophile with
the aim to further functionalize the heterocycle ring and
to obtain precursors of 6-aminoperhydro-1,4-diazepines
variously substituted at the 6-position. First, simple halo
and pseudohalo compounds (e.g., short aliphatic chlorides
and bromides, mesylates, tosylates) were used as substrates
for common substitution reactions. However, no forma-
tion of the desired products or any other byproduct was
observed. The attempts of using carbonyl or carboxyl
derivatives (including acetone, acetonitrile, ethyl acetate)
for carbonyl addition reactions were also unsuccessful.
Instead, a Michael addition followed the retro-Henry
reaction when two molar equivalents of an acrylic com-
pound were added along with t-BuOK in THF. The
corresponding products were formed within a few hours
in good yields and relatively pure. The results obtained
with several commercial acrylic compounds as well as acrylic
derivatives synthesized ad hoc are reported in Table 1
(see the Supporting Information for details).
The retro-Henry reaction is well-known although rarely
employed in organic synthesis;13 it normally involves a
base-mediated process to obtain, in first instance, a carbo-
nyl compound and a stabilized carbanion. This reaction
(6) (a) Hirokawa, Y.; Horikawa, T.; Noguchi, H.; Yamamoto, K.;
Kato, S. Org. Process Res. Dev. 2002, 6, 28. (b) Hirokawa, Y.; Fujiwara,
I.; Suzuki, K.; Harada, H.; Yoshikawa, T.; Noguchi, H.; Kato, S.
J. Med. Chem. 2003, 46, 702. (c) Hirokawa, Y.; Harada, H.; Yoshikawa,
T.; Noguchi, H.; Kato, S. Chem. Pharm. Bull. 2002, 50, 941.
(7) (a) Romba, J.; Kuppert, D.; Morgenstern, B.; Neiz, C.; Steinhauser,
S.; Weyhermuller, T.; Hegetschweiler, K. Eur. J. Inorg. Chem. 2006, 314.
(b) Peralta, R. A.; Neves, A.; Bortoluzzi, A. J.; Casellato, A.; Dos Anjos,
A.; Greatti, A.; Xavier, F. R.; Szpoganicz, B. Inorg. Chem. 2005, 44,
7690.
(8) (a) Ge, S.; Bambirra, S.; Meetsma, A.; Hessen, B. Chem. Commun.
2006, 3320. (b) Ge, S.; Bambirra, S.; Meetsma, A.; Hessen, B. Organo-
metallics 2007, 26, 5278.
(9) (a) Aime, S.; Calabi, L.; Cavallotti, C.; Gianolio, E.; Giovenzana,
G. B.; Losi, P.; Maiocchi, A.; Palmisano, G.; Sisti, M. Inorg. Chem. 2004,
43, 7588. (b) Gugliotta, G.; Botta, M.; Tei, L. Org. Biomol. Chem. 2010,
8, 4569.
Adamantyl derivatives 6 and 9 were synthesized with
the aim at preparing molecules able to form inclusion
compounds with β-cyclodextrin with high affinity and
selectivity.16 The other compounds have been prepared
in order to get a series of 6-nitro-1,4-diazepines substituted
at the 6-position with protected or pseudoprotected func-
tional groups.
(10) Lattuada, L.; Barge, A.; Cravotto, G.; Giovenzana, G. B.; Tei,
L. Chem Soc. Rev. 2011, 40, 3019.
(11) (a) Padwa, A. Pure Appl. Chem. 2004, 76, 1933. (b) Domino
Reactions in Organic synthesis; Tietze, L. F., Brasche, G., Gericke, K. M.,
Eds.; Wiley-VCH: Weinheim, 2006. (c) Padwa, A.; Bur, S. K. Tetrahedron
2007, 63, 5341.
~
~
(14) (a) Camps, P.; Munoz-Torrero, D.; Munoz-Torrero, V. Tetra-
hedron 1995, 51, 6587. (b) Tanaka, S.; Oguma, Y.; Tanaka, Y.; Echizen,
H.; Masu, H.; Yamaguchi, K.; Kishikawa, K.; Kohmoto, S.; Yamamoto,
M. Synth. Commun. 2009, 39, 868.
(15) Harada, H.; Hirokawa, Y.; Morie, T.; Kato, S. Heterocycles
1995, 41, 363.
(16) Jaime, C.; Redondo, J.; Sanchez-Ferrando, F.; Virgili, A. J. Mol.
(12) Gugliotta, G.; Botta, M.; Giovenzana, G. B.; Tei, L. Bioorg.
Med. Chem. Lett. 2009, 19, 3442–3444.
ꢀ
(13) Luzzio, F. A. Tetrahedron 2001, 57, 915.
Struct. 1991, 248, 317.
Org. Lett., Vol. 14, No. 3, 2012
717

probably due to steric hindrance. To confirm this hypo-
thesis, the tandem retro-Henry/Michael reaction with ethyl
trans-2-butenoate was attempted. Analogously, the reaction
between 2 and N-ethylidenebenzylamine (a substituted
imine prepared from benzylamine and acetaldehyde) was
carried out. In both cases the reaction did not occur,
confirming our hypothesis of steric hindrance on the reac-
tive site. Thus, it can be concluded that the carbanion needs
a nonsubstituted sp2 carbon to react further.
Table 1. Tandem Retro-Henry/Michael Reaction
The validity of the tandem protocol herein reported
is further confirmed in view of the alternative pathway
to prepare the same type of compounds, i.e., via the for-
mation of a suitable γ-nitroester or β-nitroamine, followed
by cyclization in the presence of paraformaldehyde and
N,N0-dibenzylethylenediamine.12 In fact, besides adding
a synthetic step, this procedure results disadvantageous
because the increased sterical hindrance of the nitro-
derivative favors the formation of the byproduct 1,3-dibenzy-
limidazolidine thus lowering the final yield, as observed
previously for the synthesis of similar compounds
(e.g., 1,4,6-tribenzyl-6-nitroperhydro-1,4-diazepine from
1-(2-nitroethyl)benzene).17
The synthesis of 5in one step by double-Mannich/Michael
reaction was also attempted using N,N0-dibenzylethylendia-
mine, paraformaldehyde, nitromethane, and tert-butyl acry-
late to allow the cyclization and then the Michael addition to
the nitronate. A one-step reaction was in fact successfully
exploited for the synthesis of 1 by double nitro-Mannich/
Henry reactions with nitromethane and excess of
paraformaldehyde.12 However, in this case, the desired
6-substituted nitrodiazepine formed only in negligible
amount, whereas the main products were 1, 1,4-dibenzyl-6-
nitroperhydro-1,4-diazepine and 1,3-dibenzylimidazolidine.
In order to investigate whether an amine could act at
the same time as reagent, base and solvent in the tandem
retro-Henry/Mannich reaction, nitrodiazepine 1 was re-
acted with benzylamine. In Table 3, the result obtained
using benzylamine only (entry 3) is compared with the
yields of the reactions carried out under other conditions
(entries 1 and 2).
entry
R
R0
product
yield (%)
1
2
3
4
5
6
7
COOMe
COOMe
COOtBu
COOCH2Ad
CONH2
CN
H
3
4
5
6
7
8
9
90
92
74
44
81
77
31
Me
H
H
H
H
CONHAd
H
It must be noted that Michael addition does not take
place with R,β-usaturated aldehydes or ketones: indeed,
when acrolein, 1-penten-3-one, 4-hexen-3-one or 2-cyclo-
hexenone were used, the nitronate was recovered comple-
tely unreacted.
The retro-Henry reaction was successfully followed by
a Mannich reaction when nitrodiazepine 1 was mixed with
a primary or secondary amine and paraformaldehyde in
the presence of a strong base. Alsofor thistandem reaction,
yields and purities of the products obtained from most
amines were satisfactory (Table 2).
Table 2. Tandem Retro-Henry/Mannich Reaction
entry
R
R0
product
yield (%)
1
3
3
4
5
6
C
12H25
H
H
H
H
10
11
12
13
14
15
68
51
42
29
73
71
Table 3. Tandem Retro-Henry/Mannich Reaction with Benzy-
lamine
CH2COOEt
CH2CH2NHBOC
PhCH2
ꢀ(CH2)5ꢀ
ꢀCH2CH2OCH2CH2ꢀ
When considering the reactivity of the nitronate ob-
tained after retro-Henry reaction with 1, it can be envi-
saged that the succeeding reaction occurs only with
acrylates or with imine intermediates obtained during the
Mannich reaction between the amines and paraformalde-
hyde. Simple substitution with halo- or pseudohalocom-
pounds or addition to carbonyl derivatives do not take place
entry
base
HCHO
solvent
THF
product yield (%)
1
2
3
t-BuOK
yes
yes
no
13
13
13
29
16
27
PhCH2NH2
PhCH2NH2
THF
PhCH2NH2
(17) Giovenzana, G. B.; Palmisano, G.; Sisti, M.; Cavallotti, C.;
Aime, S.; Calabi, L.; Swenson, R.; Kondareddiar, R.; Lattuada L.;
Morosini, P. WO2006136564 (A1), 2006.
According to these results, the tandem retro-Henry/
Mannich reaction can indeed be run using an amine which
718
Org. Lett., Vol. 14, No. 3, 2012

acts contemporaneously as base, reagent, and solvent,
leading to the desired product with a yield comparable
to those achieved through the other synthetic patways.
Thus, it can be summarized that (1) the OH proton of 1
is acidic enough to be removed by a base weaker than
t-BuOꢀ (this confirms our previous hypothesis that, dur-
ing hydrogenolysis of the nitrodiazepine 1, the retro-Henry
reaction may occur and thus acetic acid has to be used in
order to avoid this side reaction)12 and (2) formaldehyde is
formed in situ as a consequence of the initial retro-Henry
reaction.
MeOH and 3 molar equiv of acetic acid leading to the
aminodiazepine 17 (Scheme 3).
Scheme 3. Hydrogenolysis of Nitrodiazepine 5
As an example of continuation toward the preparation
of applicable multifunctional compounds, the nitro group
of the tert-butyl ester derivative 5 was selectively reduced
by hydrogenation in the presence of Raney-nickel (Scheme 2):
the reaction leads to 6-aminodiazepine 16 protected with
benzyl groups at the ring nitrogen atoms and with a tert-
butyl ester on the pendant arm. Such a reaction would
allow to achieve a variety of 6-aminoperhydro-1,4-diaze-
pines further functionalized at the 6-position.
In summary, a novel synthetic access to 6-substituted
6-nitroperhydro-1,4-diazepines, relying on a simple proce-
dure involving the formation of a stable carbanion via
retro-Henry reaction, followed by either Michael or Man-
nich reactions, has been reported. The versatility of the
approaches was tested with several acrylic derivatives and
with different primary or secondary amines. The tandem
retro-Henry/Mannich reaction of N,N0-dibenzyl-6-hydro-
xymethyl-6-nitroperhydro-1,4-diazepine with only benzy-
lamine further simplifies this procedure. Moreover, the selec-
tive hydrogenation of the nitro group demonstrates the
versatility of this class of compounds: the primary amine
obtained can be further functionalized in the presence
of other orthogonally protected functional groups.
Analogously, exhaustive hydrogenation allowed to
obtain an unprotected aminodiazepine suitable for
further modification.
Scheme 2. Selective Reduction of the Nitro Group of 5
Acknowledgment. This research was supported by
funding from Regione Piemonte (Nano IGT and PIIMDMT
projects). ESF COST Action D38 is also acknowledged.
Finally, as demonstrated by the synthesis of AAZTA
and other similar derivatives,9,12 the complete hydrogeno-
lysis of these 6-substituted-6-nitro-1,4-dibenzylperhydro-
1,4-diazepines leads to the free amines that can be further
alkylated with tert-butyl bromoacetate in order to obtain a
series of bifunctional chelating agents useful for bioconju-
gation reactions. Although such a protocol is currently
under investigation and optimization, the complete hydro-
genation of 5 was carried out with 10% Pd/C catalyst in
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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